| 1. |
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| 2. |
- Backman, Samuel, et al.
(författare)
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The Evolutionary History of Metastatic Pancreatic Neuroendocrine Tumours Reveals a Therapy Driven Route to High-Grade Transformation.
- 2024
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Ingår i: medRxiv : the preprint server for health sciences.
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Tidskriftsartikel (refereegranskat)abstract
- Tumour evolution with acquisition of more aggressive disease characteristics is a hallmark of disseminated cancer. Metastatic pancreatic neuroendocrine tumours (PanNETs) in particular, show frequent progression from a low/intermediate to a high-grade disease. To understand the molecular mechanisms underlying this phenomenon, we performed multi-omics analysis of 32 longitudinal samples from six metastatic PanNET patients. Following MEN1 inactivation, PanNETs exhibit genetic heterogeneity on both spatial and temporal dimensions with parallel and convergent tumuor evolution involving the ATRX/DAXX and mTOR pathways. Following alkylating chemotherapy treatment, some PanNETs develop mismatch repair deficiency and acquire a hypermutator phenotype. This DNA hypermutation phenotype was only found in cases that also showed transformation into a high-grade PanNET. Overall, our findings contribute to broaden the understanding of metastatic PanNET, and suggests that therapy driven disease evolution is an important hallmark of this disease.
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| 3. |
- Bolin, Karin, et al.
(författare)
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Variants in BANK1 are associated with lupus nephritis of European ancestry
- 2021
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Ingår i: Genes and Immunity. - : Springer Nature. - 1466-4879 .- 1476-5470. ; 22:3, s. 194-202
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Tidskriftsartikel (refereegranskat)abstract
- The genetic background of lupus nephritis (LN) has not been completely elucidated. We performed a case-only study of 2886 SLE patients, including 947 (33%) with LN. Renal biopsies were available from 396 patients. The discovery cohort (Sweden, n = 1091) and replication cohort 1 (US, n = 962) were genotyped on the Immunochip and replication cohort 2 (Denmark/Norway, n = 833) on a custom array. Patients with LN, proliferative nephritis, or LN with end-stage renal disease were compared with SLE without nephritis. Six loci were associated with LN (p < 1 × 10−4, NFKBIA, CACNA1S, ITGA1, BANK1, OR2Y, and ACER3) in the discovery cohort. Variants in BANK1 showed the strongest association with LN in replication cohort 1 (p = 9.5 × 10−4) and proliferative nephritis in a meta-analysis of discovery and replication cohort 1. There was a weak association between BANK1 and LN in replication cohort 2 (p = 0.052), and in the meta-analysis of all three cohorts the association was strengthened (p = 2.2 × 10−7). DNA methylation data in 180 LN patients demonstrated methylation quantitative trait loci (meQTL) effects between a CpG site and BANK1 variants. To conclude, we describe genetic variations in BANK1 associated with LN and evidence for genetic regulation of DNA methylation within the BANK1 locus. This indicates a role for BANK1 in LN pathogenesis.
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| 4. |
- Carlsson Almlöf, Jonas, et al.
(författare)
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Contributions of de novo variants to systemic lupus erythematosus
- 2021
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Ingår i: European Journal of Human Genetics. - : Springer Nature. - 1018-4813 .- 1476-5438. ; 29:1, s. 184-193
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Tidskriftsartikel (refereegranskat)abstract
- By performing whole-genome sequencing in a Swedish cohort of 71 parent-offspring trios, in which the child in each family is affected by systemic lupus erythematosus (SLE, OMIM 152700), we investigated the contribution of de novo variants to risk of SLE. We found de novo single nucleotide variants (SNVs) to be significantly enriched in gene promoters in SLE patients compared with healthy controls at a level corresponding to 26 de novo promoter SNVs more in each patient than expected. We identified 12 de novo SNVs in promoter regions of genes that have been previously implicated in SLE, or that have functions that could be of relevance to SLE. Furthermore, we detected three missense de novo SNVs, five de novo insertion-deletions, and three de novo structural variants with potential to affect the expression of genes that are relevant for SLE. Based on enrichment analysis, disease-affecting de novo SNVs are expected to occur in one-third of SLE patients. This study shows that de novo variants in promoters commonly contribute to the genetic risk of SLE. The fact that de novo SNVs in SLE were enriched to promoter regions highlights the importance of using whole-genome sequencing for identification of de novo variants.
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| 5. |
- Elfving, Hedvig, et al.
(författare)
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Evaluation of NTRK immunohistochemistry as a screening method for NTRK gene fusion detection in non-small cell lung cancer
- 2021
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Ingår i: Lung Cancer. - : Elsevier. - 0169-5002 .- 1872-8332. ; 151, s. 53-59
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The small molecule inhibitors larotrectinib and entrectinib have recently been approved as cancer agnostic drugs in patients with tumours harbouring a rearrangement of the neurotrophic tropomyosin receptor kinase (NTRK). These oncogenic fusions are estimated to occur in 0.1-3 % of non-small cell lung cancers (NSCLC). Although molecular techniques are most reliable for fusion detection, immunohistochemical analysis is considered valuable for screening. Therefore, we evaluated the newly introduced diagnostic immunohistochemical assay (clone EPR17341) on a representative NSCLC cohort.Methods: Cancer tissue from 688 clinically and molecularly extensively annotated NSCLC patients were comprised on tissue microarrays and stained with the pan-TRK antibody clone EPR17341. Positive cases were further analysed with the TruSight Tumor 170 RNA assay (Illumina). Selected cases were also tested with a NanoString NTRK fusion assay. For 199 cases, NTRK RNA expression data were available from previous RNA sequencing analysis.Results: Altogether, staining patterns for 617 NSCLC cases were evaluable. Of these, four cases (0.6 %) demonstrated a strong diffuse cytoplasmic and membranous staining, and seven cases a moderate staining (1.1 %). NanoString or TST170-analysis could not confirm an NTRK fusion in any of the IHC positive cases, or any of the cases with high mRNA levels. In the four cases with strong staining intensity in the tissue microarray, whole section staining revealed marked heterogeneity of NTRK protein expression.Conclusion: The presence of NTRK fusion genes in non-small cell lung cancer is exceedingly rare. The use of the immunohistochemical NTRK assay will result in a small number of false positive cases. This should be considered when the assay is applied as a screening tool in clinical diagnostics.
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| 6. |
- Gyger, Samuel, et al.
(författare)
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Metropolitan single-photon distribution at 1550 nm for random number generation
- 2022
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Ingår i: Applied Physics Letters. - : AIP Publishing. - 0003-6951 .- 1077-3118. ; 121:19, s. 194003-
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Tidskriftsartikel (refereegranskat)abstract
- Quantum communication networks will connect future generations of quantum processors, enable metrological applications, and provide security through quantum key distribution. We present a testbed that is part of the municipal fiber network in the greater Stockholm metropolitan area for quantum resource distribution through a 20 km long fiber based on semiconductor quantum dots emitting in the telecom C-band. We utilize the service to generate random numbers passing the NIST test suite SP800-22 at a subscriber 8 km outside of the city with a bit rate of 23.4 kbit/s.
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| 7. |
- Gyger, Samuel, et al.
(författare)
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Metropolitan Single-Photon Distribution at 1550 nm for Random Number Generation
- 2023
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Ingår i: 2023 Conference on Lasers and Electro-Optics, CLEO 2023. - : Institute of Electrical and Electronics Engineers Inc..
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Konferensbidrag (refereegranskat)abstract
- Quantum communication networks are used for QKD and metrological applications. We present research connecting two nodes ≈ 20 kilometers apart over the municipal fiber network using semiconductor quantum dots emitting at 1550 nm.
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| 8. |
- Lundtoft, Christian, et al.
(författare)
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Complement C4 Copy Number Variation is Linked to SSA/Ro and SSB/La Autoantibodies in Systemic Inflammatory Autoimmune Diseases
- 2022
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Ingår i: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 74:8, s. 1440-1450
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Tidskriftsartikel (refereegranskat)abstract
- Objective Copy number variation of the C4 complement components, C4A and C4B, has been associated with systemic inflammatory autoimmune diseases. This study was undertaken to investigate whether C4 copy number variation is connected to the autoimmune repertoire in systemic lupus erythematosus (SLE), primary Sjogrens syndrome (SS), or myositis. Methods Using targeted DNA sequencing, we determined the copy number and genetic variants of C4 in 2,290 well-characterized Scandinavian patients with SLE, primary SS, or myositis and 1,251 healthy controls. Results A prominent relationship was observed between C4A copy number and the presence of SSA/SSB autoantibodies, which was shared between the 3 diseases. The strongest association was detected in patients with autoantibodies against both SSA and SSB and 0 C4A copies when compared to healthy controls (odds ratio [OR] 18.0 [95% confidence interval (95% CI) 10.2-33.3]), whereas a weaker association was seen in patients without SSA/SSB autoantibodies (OR 3.1 [95% CI 1.7-5.5]). The copy number of C4 correlated positively with C4 plasma levels. Further, a common loss-of-function variant in C4A leading to reduced plasma C4 was more prevalent in SLE patients with a low copy number of C4A. Functionally, we showed that absence of C4A reduced the individuals capacity to deposit C4b on immune complexes. Conclusion We show that a low C4A copy number is more strongly associated with the autoantibody repertoire than with the clinically defined disease entities. These findings may have implications for understanding the etiopathogenetic mechanisms of systemic inflammatory autoimmune diseases and for patient stratification when taking the genetic profile into account.
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| 9. |
- Lundtoft, Christian, et al.
(författare)
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Function of multiple sclerosis-protective HLA class I alleles revealed by genome-wide protein-quantitative trait loci mapping of interferon signalling
- 2020
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 16:10
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Tidskriftsartikel (refereegranskat)abstract
- Interferons (IFNs) are cytokines that are central to the host defence against viruses and other microorganisms. If not properly regulated, IFNs may contribute to the pathogenesis of inflammatory autoimmune, or infectious diseases. To identify genetic polymorphisms regulating the IFN system we performed an unbiased genome-wide protein-quantitative trait loci (pQTL) mapping of cell-type specific type I and type II IFN receptor levels and their responses in immune cells from 303 healthy individuals. Seven genome-wide significant (p < 5.0E-8) pQTLs were identified. Two independent SNPs that tagged the multiple sclerosis (MS)-protective HLA class I alleles A*02/A*68 and B*44, respectively, were associated with increased levels of IFNAR2 in B and T cells, with the most prominent effect in IgD–CD27+ memory B cells. The increased IFNAR2 levels in B cells were replicated in cells from an independent set of healthy individuals and in MS patients. Despite increased IFNAR2 levels, B and T cells carrying the MS-protective alleles displayed a reduced response to type I IFN stimulation. Expression and methylation-QTL analysis demonstrated increased mRNA expression of the pseudogene HLA-J in B cells carrying the MS-protective class I alleles, possibly driven via methylation-dependent transcriptional regulation. Together these data suggest that the MS-protective effects of HLA class I alleles are unrelated to their antigen-presenting function, and propose a previously unappreciated function of type I IFN signalling in B and T cells in MS immune-pathogenesis.Author summaryGenetic association studies have been very successful in identifying disease-associated single nucleotide polymorphisms (SNPs), but it has been challenging to define the molecular mechanisms underlying these associations. As interferons (IFNs) have a central role in the immune system, we hypothesized that some of the SNPs associated to immune-mediated diseases would affect the IFN system. By combining genetic data with characterization of interferon receptor levels and their responses on the protein level in immune cells from 303 genotyped healthy individuals, we show that two SNPs tagging the HLA class I alleles A*02/A*68 and B*44 are associated with a decreased response to type I IFN stimulation in B cells and T cells. Notably, both HLA-A*02 and HLA-B*44 confer protection from developing multiple sclerosis (MS), which is a chronic inflammatory neurologic disease. In addition to suggesting a pathogenic role of enhanced type I interferon signalling in B cells and T cells in MS, our data emphasize the fact that genetic associations in the HLA locus can affect functions not directly associated to antigen presentation, which conceptually may be important for other diseases genetically associated to the HLA locus.
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| 10. |
- Smeds, Patrik, et al.
(författare)
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Hydra-genetics, a modular framework for bioinformatics pipeline development
- 2024
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Ingår i: European Journal of Human Genetics. - : Nature Portfolio. - 1018-4813 .- 1476-5438. ; 32:Suppl. 1, s. 675-676
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Processing information from massively parallel sequencing/next-generation sequencing (NGS) data involves several steps that transform millions of rows of input data into more accessible genetic information. The combination of bioinformatics tools that extract all requested information for a particular clinical/research application, how they are tuned and the order in which they are executed constitute a bioinformatics pipeline. Software is often reused in several pipelines and regularly updated. For clinically validated NGS pipelines it may be challenging when individual components of several pipelines needs updating or when tools are replaced with new applications.Methods: The Hydra-genetics framework takes advantage of version controlled Snakemake modules. Pipeline steps are split into modules that can be configured and tested individually. The modules can be combined to build complete bioinformatics analyses, or be added to existing pipelines. All modules are subjected to extensive testing to ensure that new releases do not unexpectedly break existing pipelines or deviate from guidelines and best practices on how to write code.Results: Bioinformaticians from five Genomics Medicine Sweden centers used Hydra-genetics to develop the bioinformatics pipeline for the comprehensive solid tumor panel, GMS560. The pipeline analyses tumor DNA and/or RNA data and generates information on genetic variation including complex biomarkers such as tumor mutation burden and microsatellite instability. It is validated and in clinical use.Conclusions: The Hydra-genetics framework provides a platform for structured bioinformatics pipeline development and facilitates joint development projects involving multiple partners. It makes clinical pipeline development easier, faster and more structured.
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